The endoplasmic reticulum acetyltransferases ATase1/NAT8B and ATase2/NAT8 are differentially regulated to adjust engagement of the secretory pathway

AbstractN ε‐lysine acetylation of nascent glycoproteins within the endoplasmic reticulum (ER) lumen regulates the efficiency of the secretory pathway. The ER acetylation machinery consists of the membrane transporter, acetyl‐CoA transporter 1 (AT‐1/SLC33A1), and two acetyltransferases, ATase1/NAT8B and ATase2/NAT8. Dysfunctional ER acetylation is associated with severe neurological diseases with duplication ofAT ‐1/SLC33A1 being associated with autism spectrum disorder, intellectual disability, and dysmorphism. Neuron ‐specific AT‐1 overexpression in the mouse alters neuron morphology and function, causing an autism‐like phenotype, indicating that ER acetylation plays a key role in neurophysiology. As such, characterizing the molecular mechanisms that regulate the acetylation machinery could reveal critical information about its biology. By using structure‐biochemistry approaches, we discovered that ATase1 and ATase2 share enzymatic properties but differ in that ATase1 is post‐translationally regulated via acetylation. Furthermore, gene expression studies revealed that the promoters ofAT ‐1,ATase1, andATase2 contain functional binding sites for the neuron ‐related transcription factors cAMP response element‐binding protein (CREB) and the immediate early genes c‐FOS and c‐JUN, and thatATase1 andATase2 exhibit additional modes of transcriptional regulation relevant to aging and Alzheimer's disease. In vivo rodent gene expression experiments r...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research

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Contributors : Yanina I Pachimal ; Adva Hadar ; Iris Grigg ; Vlasta Korenkova ; Oxana Kapitansky ; Gidon Karmon ; Michael Gershovits ; Laura C Sayas ; Frank R Kooy ; Johannes Attems ; David Gurwitz ; Illana GozesSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensDe novo mutated ADNP is a most prevalent gene driving syndromic autism with intellectual disability. Using droplet digital PCR and RNA sequencing we identified somatic mutations in ADNP and in other genes in the olfactory bulb and hipocampi of Alzheimer's disease (AD) patients.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research
Molecular Psychiatry, Published online: 30 October 2019; doi:10.1038/s41380-019-0563-5Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study
Source: Molecular Psychiatry - Category: Psychiatry Authors: Source Type: research
ánchez As the leading causes of human disability and mortality, neurological diseases affect millions of people worldwide and are on the rise. Although the general roles of several signaling pathways in the pathogenesis of neurodegenerative disorders have so far been identified, the exact pathophysiology of neuronal disorders and their effective treatments have not yet been precisely elucidated. This requires multi-target treatments, which should simultaneously attenuate neuronal inflammation, oxidative stress, and apoptosis. In this regard, astaxanthin (AST) has gained growing interest as a multi-target pharmac...
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Source: Frontiers in Psychiatry - Category: Psychiatry Source Type: research
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Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
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